Platelets mediate the critical first-step in hemostasis (Bahou, W F, (2003) Curr Top Dev Biol 54, 343-369; Bahou, W F (2002) Nat Med 8, 1082-1083), and qualitative platelet disorders cause bleeding syndromes (Bahou, W F (2006) Genomics and Clinical Medicine (ed D. Kumar) 221-248 (Oxford University Press). Quantitative disorders of platelet number are associated with bleeding (thrombocytopenia; low platelet count), or thrombohemorrhage (thrombocythemia; high platelet count) (Vainchenker W et al., (2011) Blood 118(7):1723-1735; Kaser A, et al. (2001) Blood 98(9):2720-2725; Kaushansky K (2008) Blood 111(3):981-986; Bahou W F (2006) Genomics and Clinical Medicine, ed Kumar D (Oxford University Press, Oxford), pp 221-248; Bahou. W F (2012) Thromb Res 129 Suppl 1:S38-45; Debili N, et al. (1996) Blood 88(4):1284-1296; James C, et al. (2005) Nature 434(7037):1144-1148; Nangalia J, et al. (2013) The New England journal of medicine 369(25):2391-2405; Klampfl T, et al. (2013) The New England journal of medicine 369(25):2379-2390)
About 1×1011 platelets are produced daily by megakaryocyte (MK) formation, which is largely controlled by the TPO/c-MPL (thrombopoietin/c-myeloproliferative ligand receptor) axis, and derived from common bi-potent megakaryocyte-erythrocyte progenitors (MEP) (Debili, N. et al. (1996) Blood 88, 1284-1296). Human blood platelets stop bleeding, and low platelet counts cause life-threatening hemorrhage. Approaches to temporarily correct low platelet counts include platelet transfusions from donors which are difficult to obtain and are costly, and medications. However, medications are known to be associated with adverse effects such as platelet activation, blood clotting, worsening of platelet counts, and bone marrow scarring.
To date, approaches for enhancing platelet production have focused on the TPO/c-MPL axis. Three general classes of second-generation TPOs are currently in development: (i) TPO peptide mimetics, (ii) TPO nonpeptide mimetics, and (iii) TPO antibody mimetics. While these drugs show efficacy in enhancing platelet production, their direct receptor binding/activation mechanism(s) have raised concerns relative to platelet activation, secondary thromboembolic complications, rebound thrombocytopenia, and increased bone marrow reticulin formation (Liebman, H A and Pullarkat, V (2011) Hematology Am Soc Hematol Educ Program 2011, 384-390).